Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: A north central cancer treatment group study

Evanthia Galanis, Jan C. Buckner, Matthew J. Maurer, Jeffrey I. Kreisberg, Karla Ballman, J. Boni, Josep M. Peralba, Robert B. Jenkins, Shaker R. Dakhil, Roscoe F. Morton, Kurt A. Jaeckle, Bernd W. Scheithauer, Janet Dancey, Manuel Hidalgo, Daniel J. Walsh

Research output: Contribution to journalArticle

602 Citations (Scopus)

Abstract

Background: Temsirolimus (CCI-779) is a small-molecule inhibitor of the mammalian target of rapamycin (mTOR) and represents a rational therapeutic target against glioblastoma multiforme (GBM). Methods: Recurrent GBM patients with ≤ 1 chemotherapy regimen for progressive disease were eligible. Temsirolimus was administered in a 250-mg intravenous dose weekly. Results: Sixty-five patients were treated. The incidence of grade 3 or higher nonhematologic toxicity was 51%, and consisted mostly of hypercholesterolemia (11%), hypertriglyceridemia (8%), and hyperglycemia (8%). Grade 3 hematologic toxicity was observed in 11% of patients. Temsirolimus peak concentration (Cmax), and sirolimus Cmax and area under the concentration-time curve were decreased in patients receiving p450 enzyme-inducing anticonvulsants (EIACs) by 73%, 47%, and 50%, respectively, but were still within the therapeutic range of preclinical models. Twenty patients (36%) had evidence of improvement in neuroimaging, consisting of decrease in T2 signal abnormality +/- decrease in T1 gadolinium enhancement, on stable or reduced steroid doses. Progression-free survival at 6 months was 7.8% and median overall survival was 4.4 months. Median time to progression (TTP) for all patients was 2.3 months and was significantly longer for responders (5.4 months) versus nonresponders (1.9 months). Development of grade 2 or higher hyperlipidemia in the first two treatment cycles was associated with a higher percentage of radiographic response (71% v 31%; P = .04). Significant correlation was observed between radiographic improvement and high levels of phosphorylated p70s6 kinase in baseline tumor samples (P = .04). Conclusion: Temsirolimus is well tolerated in recurrent GBM patients. Despite the effect of EIACs on temsirolimus metabolism, therapeutic levels were achieved. Radiographic improvement was observed in 36% of temsirolimus-treated patients, and was associated with significantly longer TTP. High levels of phosphorylated p70s6 kinase in baseline tumor samples appear to predict a patient population more likely to derive benefit from treatment. These findings should be validated in other studies of mTOR inhibitors.

Original languageEnglish (US)
Pages (from-to)5294-5304
Number of pages11
JournalJournal of Clinical Oncology
Volume23
Issue number23
DOIs
StatePublished - Dec 1 2005

Fingerprint

Glioblastoma
Neoplasms
Sirolimus
Therapeutics
Anticonvulsants
Phosphotransferases
temsirolimus
Hypertriglyceridemia
Gadolinium
Hypercholesterolemia
Hyperlipidemias
Neuroimaging
Hyperglycemia
Cytochrome P-450 Enzyme System
Disease-Free Survival
Steroids
Drug Therapy
Survival
Incidence
Enzymes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Galanis, E., Buckner, J. C., Maurer, M. J., Kreisberg, J. I., Ballman, K., Boni, J., ... Walsh, D. J. (2005). Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: A north central cancer treatment group study. Journal of Clinical Oncology, 23(23), 5294-5304. https://doi.org/10.1200/JCO.2005.23.622
Galanis, Evanthia ; Buckner, Jan C. ; Maurer, Matthew J. ; Kreisberg, Jeffrey I. ; Ballman, Karla ; Boni, J. ; Peralba, Josep M. ; Jenkins, Robert B. ; Dakhil, Shaker R. ; Morton, Roscoe F. ; Jaeckle, Kurt A. ; Scheithauer, Bernd W. ; Dancey, Janet ; Hidalgo, Manuel ; Walsh, Daniel J. / Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme : A north central cancer treatment group study. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 23. pp. 5294-5304.
@article{dea6d8167ee2429abb173da4730c02da,
title = "Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: A north central cancer treatment group study",
abstract = "Background: Temsirolimus (CCI-779) is a small-molecule inhibitor of the mammalian target of rapamycin (mTOR) and represents a rational therapeutic target against glioblastoma multiforme (GBM). Methods: Recurrent GBM patients with ≤ 1 chemotherapy regimen for progressive disease were eligible. Temsirolimus was administered in a 250-mg intravenous dose weekly. Results: Sixty-five patients were treated. The incidence of grade 3 or higher nonhematologic toxicity was 51{\%}, and consisted mostly of hypercholesterolemia (11{\%}), hypertriglyceridemia (8{\%}), and hyperglycemia (8{\%}). Grade 3 hematologic toxicity was observed in 11{\%} of patients. Temsirolimus peak concentration (Cmax), and sirolimus Cmax and area under the concentration-time curve were decreased in patients receiving p450 enzyme-inducing anticonvulsants (EIACs) by 73{\%}, 47{\%}, and 50{\%}, respectively, but were still within the therapeutic range of preclinical models. Twenty patients (36{\%}) had evidence of improvement in neuroimaging, consisting of decrease in T2 signal abnormality +/- decrease in T1 gadolinium enhancement, on stable or reduced steroid doses. Progression-free survival at 6 months was 7.8{\%} and median overall survival was 4.4 months. Median time to progression (TTP) for all patients was 2.3 months and was significantly longer for responders (5.4 months) versus nonresponders (1.9 months). Development of grade 2 or higher hyperlipidemia in the first two treatment cycles was associated with a higher percentage of radiographic response (71{\%} v 31{\%}; P = .04). Significant correlation was observed between radiographic improvement and high levels of phosphorylated p70s6 kinase in baseline tumor samples (P = .04). Conclusion: Temsirolimus is well tolerated in recurrent GBM patients. Despite the effect of EIACs on temsirolimus metabolism, therapeutic levels were achieved. Radiographic improvement was observed in 36{\%} of temsirolimus-treated patients, and was associated with significantly longer TTP. High levels of phosphorylated p70s6 kinase in baseline tumor samples appear to predict a patient population more likely to derive benefit from treatment. These findings should be validated in other studies of mTOR inhibitors.",
author = "Evanthia Galanis and Buckner, {Jan C.} and Maurer, {Matthew J.} and Kreisberg, {Jeffrey I.} and Karla Ballman and J. Boni and Peralba, {Josep M.} and Jenkins, {Robert B.} and Dakhil, {Shaker R.} and Morton, {Roscoe F.} and Jaeckle, {Kurt A.} and Scheithauer, {Bernd W.} and Janet Dancey and Manuel Hidalgo and Walsh, {Daniel J.}",
year = "2005",
month = "12",
day = "1",
doi = "10.1200/JCO.2005.23.622",
language = "English (US)",
volume = "23",
pages = "5294--5304",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "23",

}

Galanis, E, Buckner, JC, Maurer, MJ, Kreisberg, JI, Ballman, K, Boni, J, Peralba, JM, Jenkins, RB, Dakhil, SR, Morton, RF, Jaeckle, KA, Scheithauer, BW, Dancey, J, Hidalgo, M & Walsh, DJ 2005, 'Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: A north central cancer treatment group study', Journal of Clinical Oncology, vol. 23, no. 23, pp. 5294-5304. https://doi.org/10.1200/JCO.2005.23.622

Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme : A north central cancer treatment group study. / Galanis, Evanthia; Buckner, Jan C.; Maurer, Matthew J.; Kreisberg, Jeffrey I.; Ballman, Karla; Boni, J.; Peralba, Josep M.; Jenkins, Robert B.; Dakhil, Shaker R.; Morton, Roscoe F.; Jaeckle, Kurt A.; Scheithauer, Bernd W.; Dancey, Janet; Hidalgo, Manuel; Walsh, Daniel J.

In: Journal of Clinical Oncology, Vol. 23, No. 23, 01.12.2005, p. 5294-5304.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme

T2 - A north central cancer treatment group study

AU - Galanis, Evanthia

AU - Buckner, Jan C.

AU - Maurer, Matthew J.

AU - Kreisberg, Jeffrey I.

AU - Ballman, Karla

AU - Boni, J.

AU - Peralba, Josep M.

AU - Jenkins, Robert B.

AU - Dakhil, Shaker R.

AU - Morton, Roscoe F.

AU - Jaeckle, Kurt A.

AU - Scheithauer, Bernd W.

AU - Dancey, Janet

AU - Hidalgo, Manuel

AU - Walsh, Daniel J.

PY - 2005/12/1

Y1 - 2005/12/1

N2 - Background: Temsirolimus (CCI-779) is a small-molecule inhibitor of the mammalian target of rapamycin (mTOR) and represents a rational therapeutic target against glioblastoma multiforme (GBM). Methods: Recurrent GBM patients with ≤ 1 chemotherapy regimen for progressive disease were eligible. Temsirolimus was administered in a 250-mg intravenous dose weekly. Results: Sixty-five patients were treated. The incidence of grade 3 or higher nonhematologic toxicity was 51%, and consisted mostly of hypercholesterolemia (11%), hypertriglyceridemia (8%), and hyperglycemia (8%). Grade 3 hematologic toxicity was observed in 11% of patients. Temsirolimus peak concentration (Cmax), and sirolimus Cmax and area under the concentration-time curve were decreased in patients receiving p450 enzyme-inducing anticonvulsants (EIACs) by 73%, 47%, and 50%, respectively, but were still within the therapeutic range of preclinical models. Twenty patients (36%) had evidence of improvement in neuroimaging, consisting of decrease in T2 signal abnormality +/- decrease in T1 gadolinium enhancement, on stable or reduced steroid doses. Progression-free survival at 6 months was 7.8% and median overall survival was 4.4 months. Median time to progression (TTP) for all patients was 2.3 months and was significantly longer for responders (5.4 months) versus nonresponders (1.9 months). Development of grade 2 or higher hyperlipidemia in the first two treatment cycles was associated with a higher percentage of radiographic response (71% v 31%; P = .04). Significant correlation was observed between radiographic improvement and high levels of phosphorylated p70s6 kinase in baseline tumor samples (P = .04). Conclusion: Temsirolimus is well tolerated in recurrent GBM patients. Despite the effect of EIACs on temsirolimus metabolism, therapeutic levels were achieved. Radiographic improvement was observed in 36% of temsirolimus-treated patients, and was associated with significantly longer TTP. High levels of phosphorylated p70s6 kinase in baseline tumor samples appear to predict a patient population more likely to derive benefit from treatment. These findings should be validated in other studies of mTOR inhibitors.

AB - Background: Temsirolimus (CCI-779) is a small-molecule inhibitor of the mammalian target of rapamycin (mTOR) and represents a rational therapeutic target against glioblastoma multiforme (GBM). Methods: Recurrent GBM patients with ≤ 1 chemotherapy regimen for progressive disease were eligible. Temsirolimus was administered in a 250-mg intravenous dose weekly. Results: Sixty-five patients were treated. The incidence of grade 3 or higher nonhematologic toxicity was 51%, and consisted mostly of hypercholesterolemia (11%), hypertriglyceridemia (8%), and hyperglycemia (8%). Grade 3 hematologic toxicity was observed in 11% of patients. Temsirolimus peak concentration (Cmax), and sirolimus Cmax and area under the concentration-time curve were decreased in patients receiving p450 enzyme-inducing anticonvulsants (EIACs) by 73%, 47%, and 50%, respectively, but were still within the therapeutic range of preclinical models. Twenty patients (36%) had evidence of improvement in neuroimaging, consisting of decrease in T2 signal abnormality +/- decrease in T1 gadolinium enhancement, on stable or reduced steroid doses. Progression-free survival at 6 months was 7.8% and median overall survival was 4.4 months. Median time to progression (TTP) for all patients was 2.3 months and was significantly longer for responders (5.4 months) versus nonresponders (1.9 months). Development of grade 2 or higher hyperlipidemia in the first two treatment cycles was associated with a higher percentage of radiographic response (71% v 31%; P = .04). Significant correlation was observed between radiographic improvement and high levels of phosphorylated p70s6 kinase in baseline tumor samples (P = .04). Conclusion: Temsirolimus is well tolerated in recurrent GBM patients. Despite the effect of EIACs on temsirolimus metabolism, therapeutic levels were achieved. Radiographic improvement was observed in 36% of temsirolimus-treated patients, and was associated with significantly longer TTP. High levels of phosphorylated p70s6 kinase in baseline tumor samples appear to predict a patient population more likely to derive benefit from treatment. These findings should be validated in other studies of mTOR inhibitors.

UR - http://www.scopus.com/inward/record.url?scp=23944453425&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23944453425&partnerID=8YFLogxK

U2 - 10.1200/JCO.2005.23.622

DO - 10.1200/JCO.2005.23.622

M3 - Article

C2 - 15998902

AN - SCOPUS:23944453425

VL - 23

SP - 5294

EP - 5304

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 23

ER -